The application of molecular modelling studies to understand the selectivity and potency of several novel carbonic anhydrase inhibitors


Akdemir A.

the 4th International Satellite Meeting on Carbonic Anhydrase, Parma, İtalya, 14 - 17 November 2019

  • Basıldığı Şehir: Parma
  • Basıldığı Ülke: İtalya

Özet

The application of molecular modelling studies to understand the selectivity and potency of several novel carbonic anhydrase inhibitors

Atilla Akdemir

 Computer-Aided Drug Discovery Laboratory, Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, 34093 Istanbul, Turkey

 aakdemir@bezmialem.edu.tr

 

CAs are metalloenzymes that catalyse the reversible hydration of carbon dioxide to bicarbonate. Eventhough this is a simple reaction, it influences physiological pH values and provides bicarbonate for bioreactions or maintaining the ion balance.[1,2]  Many isoforms exist with different tissue distribution and reaction kinetics and thus CA isoforms are involved in different physiological processes. For example, hCA IX and XII are overexpressed in hypoxic tumour cells and are involved in the survival of those cells. CAs from pathogenic microorganisms are involved in virulence. As such, selective inhibitors of specific target CAs may be drug candidates for antimicrobial or anticancer chemotherapy agents.

In both previous and ongoing studies, we synthesized structurally novel sulfonamides and tested them against carbonic anhydrase (CA) isozymes that are considered drug targets for anticancer chemotherapeutics or antimicrobial  agents.[3] Several inhibitors have been obtained that selectively and potently inhibit tumour-associated hCA IX/XII  or pathenic CAs, while they only show poor inhibition of the widespread off-targets hCA I/II.  Molecular modelling studies have been performed to understand the reasons behind the selectivity and potency of these compounds. These results will direct our synthesis efforts in obtaining inhibitors with higher selectivity and potency.

 

References

[1]   Supuran, C.T.; Scozzafava, A. Carbonic anhydrases as targets for medicinal chemistry. Bioorganic and Medicinal Chemistry 2007, 13, 4336-4350

[2]   Supuran, C.T. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nature Reviews Drug Discovery 2008, 2, 168-181

[3]   Demir-Yazıcı, K.; Bua, S.; Akgüneş, N.M.; Akdemir, A.; Supuran, C.T. and Güzel-Akdemir, Ö. Indole-based hydrazones containing a sulfonamide moiety as selective inhibitors of tumor-associated human carbonic anhydrase isoforms IX and XII. Internationl Journal of Molecular Science 2019, 20(9), 2354